Anthracyclines are considered as one of the most effective anticancer drugs ever developed, either used as single agents or in combination therapy. Since the first isolation of doxorubicin (DOX) and daunorubicin (DNR) from the Streptomycin paucities in the 1960s, thousands of analogs have been reported. However, only a few of them have earned clinical approval, including Idarubicin (IDA, Zavedos®), Epirubicin (EPI, Farmorubicin®), Aclarubicin, Pirarubicin (Theprubicin®), and Valrubicin (Valstar®).
These drugs are natural or semi-synthetic products with similar structures and sugar moieties. For instance, DOX and DNR share the same carbon skeleton, which contains a fused tetracyclic ring and a carbohydrate motif (daunosamine). The only difference between DOX and DNR is the side chain at C14, where DNR carries a methyl group and DOX bears a primary alcohol. Although all of these anthracyclines contain similar structures, their therapeutic applications are very different. For instance, daunorubicin and idarubicin are primarily used in leukemia and lymphoma, whereas doxorubicin and epirubicin have broader anticancer activities against leukemia, lymphomas, and a variety of solid tumors including breast cancer, small cell lung cancer, cervical cancer, as well as head and neck cancer.
Although anthracyclines are widely used clinically in cancer therapy, drug resistance and cardiotoxicity limit their clinical application.
Although many mechanisms have been considered for the anticancer activity of anthracyclines, mammalian topoisomerases (specifically Top1 & Top2) are considered to be the primary molecular targets. Top1 & Top2 are ubiquitous enzymes that manage the topology of DNA during DNA replication, transcription, recombination, and chromatin remodeling. Mammalian Top1 is a single subunit enzyme that remains attached to the DNA by a tyrosyl linkage to a 3′ phosphate during the DNA strand-passing step of the reaction. In contrast, mammalian Top2 is a two subunit enzyme that introduces a transient, staggered dsDNA break into a DNA duplex, and passes another dsDNA through the break. The two subunits of Top2 are covalently attached to the DNA by tyrosyl linkages to 5′ phosphates during the strand-passing event.
Anthracyclines are generally believed to be Top2 poisons. Some reports have demonstrated that some anthracyclines also target Top 1.
Drug resistance of anthracyclines in cancer therapy is generally considered to be mediated by P-gp that is encoded by multidrug resistant gene (MDR1). P-gp is over-expressed in many drug-resistant cancer cells to actively export anthracyclines out of cancer cells, reduce intracellular drug concentration, and thus induce drug resistance in leukemia and solid tumors. Modification of the structure of anthracycline has demonstrated some success in overcoming drug resistance.